Identification and analysis of the genes responsible for inherited neurodegenerative disorders

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A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supportingly, nuclear inclusions containing expanded polyglutamines have been identified in neurons from patient brains and in neurons from transgenic mouse models of this class of neural disorders.We analyzed the consequence of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1(DN-SEK1), but not by DN-SEKI tagged with a nuclear export signal. Steady state SEKI expression itself was enhanced by two to three fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, colocalized with not only activated SEKl but also activated c-Jun. We also observed that nuclear inclusion-positive neurons from Huntington disease brains expressed SEK 1.This study provides molecular links between neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades, and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in transduction of a death signal.